http://www.jhltonline.org
Pregnancy after lung and heart-lung transplantation Mitesh V. Thakrar, MD,a,b Katie Morley, RN,a James L. Lordan, MD,a Gerard Meachery, MD,a Andrew J. Fisher, MD,a Gareth Parry, MD,a and Paul A. Corris, MDa From the aCardiopulmonary Transplantation, Institute of Transplantation, Institute of Cellular Medicine, Newcastle University and The Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, United Kingdom; and the bDepartment of Medicine, Division of Pulmonary Medicine, Southern Alberta Lung Transplant Program, University of Calgary, Calgary, Alberta, Canada.
KEYWORDS: transplantation; pregnancy; calcineurin inhibitor; spirometry; renal function
BACKGROUND: Advances in lung transplantation have enabled women to successfully undertake pregnancies. This study explored outcomes in this group, including changes in lung function, kidney function, and calcineurin inhibitor (CNI) levels. METHODS: A retrospective review identified 19 transplant recipients who had ever become pregnant at our center, and manual reviews of their medical records were completed for 14. Results of spirometry, serum creatinine, CNI doses and trough levels, and comorbidities were collected. RESULTS: Eight births occurred (42% success rate). Six patients have since died, with pregnancy contributing to 1 death. Five pregnancies were unplanned, with only 1 resulting in birth. Six pregnancies ended with spontaneous termination, and 2 were terminated for medical reasons. Mean age was 31.4 years (range, 22–39 years), and mean time from transplant was 76.2 months (range, 26–139 months). Complications included preeclampsia in 2, diabetes of pregnancy in 1, and abnormal liver enzymes in 1. Within 6 months of delivery, there were 2 cases of pneumonia, 2 cases of obliterative bronchiolitis, 1 case of tuberculosis, and 1 case of mild acute rejection. Forced expiratory volume in 1 second was stable at 3 (–1.5%; p ¼ 0.55) and 12 months (1.4%; p ¼ 0.84) after pregnancy. Mean change in Forced expiratory volume in 1 second during full-term pregnancies was –2.4% (p ¼ 0.29), and the mean change in forced vital capacity was –0.8% (p ¼ 0.55). In the first trimester, 83% of patients had a fall in creatinine, and a universal fall in CNI trough levels was seen. CONCLUSIONS: In carefully selected patients, planned pregnancy after lung transplant can be successful. Complications are common, and close monitoring of immunosuppression and renal function is needed. J Heart Lung Transplant 2014;33:593–598 r 2014 International Society for Heart and Lung Transplantation. All rights reserved.
Lung transplantation has become an ever-increasing option in the management of end-stage lung diseases, with steadily improving outcomes.1 These advances have allowed women of childbearing age to successfully undertake pregnancies, with delivery of healthy infants, but with significantly a higher risk than the general population.2–6 Given these higher risks, it has Reprint requests: Mitesh V. Thakrar, MD, University of Calgary, Peter Lougheed Hospital, 3500 26 Ave NE, Calgary, AB T1Y 6J4, Canada. Telephone: þ1-403-943-4833. Fax: þ1-403-943-4017. E-mail address: [email protected]
been advised that pregnancies should be planned in advance in this group and that teratogenic medications, such as mycophenolate mofetil, be stopped before conception.7 Furthermore, it has been advised that pregnancies should be avoided until at least 1 to 3 years after transplant.7–9 The literature remains rather scarce on a clear policy and outcomes after pregnancy in lung transplant recipients, so we present our own experience. We hypothesized that patients could successfully deliver term infants, but that significant complications might be evident through pregnancy and after. The purpose of this
1053-2498/$ - see front matter r 2014 International Society for Heart and Lung Transplantation. All rights reserved. http://dx.doi.org/10.1016/j.healun.2014.02.008
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study was to contribute to an area that requires further knowledge and improve our understanding of maternal outcomes with pregnancy, with a particular focus on changes in physiology, such as lung function, kidney function, and calcineurin inhibitor (CNI) levels, which may have a bearing on future graft function.
Methods A retrospective audit of all lung transplants ever conducted at the Freeman Hospital in Newcastle upon Tyne was undertaken. Searches of the local database identified all patients who had ever become pregnant, and their medical records were manually reviewed. Results of lung function testing, serum creatinine, CNI doses and trough levels, and any comorbidities encountered were collected. Changes in spirometry over time were compared with baseline, with calculations of 95% confidence intervals (CIs) made using Excel software (Microsoft Corp, Redmond, WA). This study was classified as an audit of clinical practice, and given that all patient information was anonymous, application to the local Ethics Review Board was not necessary according to local policy.
Results In more than 25 years’ experience, there have been 827 transplants (lung and heart-lung transplants) in 816 patients. Of these, 253 were women aged younger than 40 years, among whom there have been 19 pregnancies amongst 16 patients, leading to 8 live births (42% success rate). Complete medical records were available for 14 pregnancies, of which 6 were successful. Of the other 8 pregnancies, 6 ended in spontaneous terminations, and 2 required termination due to medical reasons (1 ectopic pregnancy and 1 unplanned pregnancy in a patient with poor lung function). Available records showed that 3 of the 14 pregnancies (21%) required assistance with fertility treatments, all of whom were aged older than 30 years. Patient 1 attempted in vitro fertilization and ultimately conceived naturally. Table 1
Patients 7 and 8 used medications to improve fertility; however, their 2 pregnancies resulted in miscarriage. Six patients died after their pregnancies, and 8 mothers remain alive (range, 3–197 months post-partum). Death in 1 patient occurred 8 months after delivery, with the patient presenting with rapidly progressive bronchiolitis obliterans syndrome (BOS) and an unplanned pregnancy at the same time; it appears as though this is the only patient in our series in whom death may be partly attributable to pregnancy. Mean age at the time of pregnancy was 31.4 years (range 22–39 years), and mean time from transplant was 76.2 months (range 26–139 months; Table 1). Immunosuppressive regimens were varied and included combinations of tacrolimus in 8, cyclosporine A in 6, azathioprine in 6, prednisone in 10, and methotrexate in 1 (unplanned pregnancy; Table 1). Most patients (93%) had pre-existing medical comorbid conditions, medical conditions that arose during pregnancy, or post-partum medical concerns. Pre-pregnancy complications included chronic kidney disease (50%), diabetes (29%), genital warts (7%), and BOS (21%, all unplanned pregnancies; Table 2). In the cases of pre-existing BOS, 1 patient became pregnant with no prior discussion about pregnancy with the transplant center. In her situation, a medically indicated termination was performed after the risks of pregnancy were outlined to her and her partner and consent was obtained. In the other patient, 2 unplanned pregnancies occurred, one of which ended in a spontaneous abortion, whereas the second delivery was successful. However, rapidly progressive BOS resulting in death complicated the pregnancy and post-partum period. Complications during pregnancy included preeclampsia in 2 (14%), diabetes of pregnancy in 1 (7%), and abnormal liver enzymes in 1 (7%). Within 6 months of delivery, there were 3 infections (21%), 3 cases of BOS (21%), and 1 mild acute rejection (7%) that did not require steroid augmentation (Table 2). With respect to the infections
Maternal Characteristics
Pt
Months post-Tx
Age at pregnancy (years)
Type of Tx
Indication for Tx
Immunosuppression
Planned or unplanned Pregnancy
1 2 3 4 5 6 7 8 9 10 11 12 13 14
139 26 71 48 62 67 126 42 60 78 119 107 101 63
39 23 38 28 29 22 39 32 37 39 37 26 31 20
SSLTx SSLTx SSLTx SSLTx SSLTx HLTx HLTx SSLTx HLTx HLTx SSLTx HLTx HLTx HLTx
Cystic fibrosis Cystic fibrosis Cystic fibrosis Cystic fibrosis Cystic fibrosis Congenital heart Congenital heart Cystic fibrosis Asthma Asthma Cystic fibrosis CTEPH Congenital heart Cystic fibrosis
Tac Tac, Pred Tac, Pred, Aza CyA, Pred, Aza CyA, Pred, Aza Mtx, CyA, Pred CyA Tac, Pred, CyA CyA, Pred CyA, Pred Tac Tac, Aza, Pred Tac, Aza Tac, Pred, Aza
Unplanned Unplanned Planned Planned Planned Unplanned Planned Planned Planned Planned Unplanned Unplanned Planned Planned
Aza, azathioprine; CyA, cyclosporine A; CTEPH, chronic thromboembolic pulmonary hypertension; HLTx, heart and lung transplant; Mtx, methotrexate; Pred, prednisone; Pt, patient; SSLTx, single sequential lung transplant; Tac, tacrolimus; Tx, transplant.
Thakrar et al. Table 2
Pregnancy After Transplantation
595
Pregnancy Outcomes Complications
Pt
Pre-existing conditions
During pregnancy
After delivery
Outcomea
1 2 3 4 5 6 7 8 9 10 11 12 13 14
BOS, ISHLT stage 1 DM CKD sage 3 CKD sage 3, DM CKD stage 3, DM BOS, ISHLT stage 3 CKD stage 3 CKD stage 3 CKD stage 3 CKD stage 4 BOS, ISHLT stage 1 Genital and peri-anal warts
DM
Pneumonia, rapid BOS
Birth Birth Miscarriage at 11 weeks Miscarriage at 12 weeks Birth Termination Termination at 6 weeks Miscarriage at 12 weeks Birth Birth Miscarriage 16 weeks Miscarriage Birth Miscarriage
A1B2 rejection Active tuberculosis Abnormal liver enzymes Worsened BOS; required TLI Ectopic pregnancy Pneumonia, BOS Preeclampsia Preeclampsia
GERD, DM
BOS
BOS, bronchiolitis obliterans syndrome; CKD, chronic kidney disease; DM, diabetes mellitus; GERD, gastroesophageal reflux disease; ISHLT, International Society of Heart and Lung Transplantation; TLI, total lymphoid irradiation. a Termination indicates medical termination; miscarriage indicates spontaneous abortion.
encountered, 2 cases of bacterial pneumonia were seen, which were easily treated with antibiotics. The third was a case of highly infectious, but fully susceptible, tuberculosis of the larynx that required 6 months of therapy, and subsequent cure was achieved. In the cases of post-partum BOS, lung function stabilized spontaneously in 2 patients with BOS stage 1. In the other, total lymphoid irradiation was required to halt progression of BOS. In patients with full-term pregnancies and in those with terminated pregnancies, spirometry nearest the time of conception was similar to that obtained at 3 and 12 months after pregnancy in all but 1 patient (Figure 1). Excluding Patient 1, who presented with severe and rapid BOS at the onset of pregnancy, mean changes in forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) at 3 months after pregnancy in all comers were, compared with baseline, –1.5% (median, –1.78%; 95% CI, –8.5% to
5.5%), and 1.4% (median, –0.35%; 95% CI, –5.0% to 7.7%), respectively (Figure 1). Similarly, at 12 months after pregnancy, mean changes in FEV1 and FVC were 1.1% (median, –1.3%; 95% CI, –3.6% to 5.8%) and 2.1% (median, –0.38%; 95% CI, –6.2% to 10.3%) compared with baseline, respectively (Figure 1). In the 6 live births that occurred, as described above, 1 patient had a severe drop in her FEV1 and FVC related to rapidly progressive BOS. However, in the remaining 5 pregnancies, lung function was relatively stable when the last spirometry measurement during pregnancy was compared with the value approximately 1 year before conception. This final gestational spirometry measurement occurred between 25 and 36 weeks’ gestation in this group. Mean change in FEV1 during pregnancy compared with baseline was –2.4% (median, –5.0%; 95% CI, –11.3% to 6.5%), and mean change in FVC was –0.8% (median,
10
Percentage Change in Spirometry
0 -10 -20 -30 -40 -50 -60 -70 -80 Baseline
Delivery Patient 1 FEV1
Patient 1 FVC
3 months post All Others FEV1
12 months post All Others FVC
Figure 1 Percentage change in spirometry after pregnancy compared with before conception in all patients. FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity.
596 Table 3
The Journal of Heart and Lung Transplantation, Vol 33, No 6, June 2014 (A) Changes in Kidney Function and Tacrolimus Doses/Levels Through Pregnancya Patient 1
Patient 2
Patient 13
Assessmentb
Cr (μmol/ liter)
Tac level
Total tac daily dose (mg)
Cr (μmol/ liter)
Tac level
Total tac daily dose (mg)
Cr (μmol/liter)
Tac level
Total tac daily dose (mg)
Baseline 1st trimester 3rd trimester
109 78 76
11.1 4 6.3
4 4 5
110 102 112
9 3.2 7.4
7 7 9
98 79 74
9.3 9.1 4.5
4 4 5
Tac, tacrolimus. a Number of patients are too low to calculate meaningful p-values. b Baseline collected 2–12 weeks before conception, 1st trimester collected before 12 weeks gestation, 3rd trimester is the last testing before delivery (26–35 weeks’ gestation).
–1.3%; 95% CI, –9.2% to 7.5%). Patients with terminations were not included in this analysis because none had spirometry in the second or third trimesters. In contrast to relatively stable lung function in these pregnancies, there was evidence of changes in serum creatinine and CNI levels. In the first trimester, creatinine fell in 5 patients, and there was a significant fall in drug levels in 5 patients. In patients receiving tacrolimus, total daily doses were increased 20% to 37.5%, although trough levels still did not meet pre-pregnancy levels (Table 3A). In contrast, those receiving cyclosporine A appeared to not receive dose adjustments, and their trough levels remained lower than baseline throughout pregnancy (Table 3B).
Discussion This review of a single center’s experience in pregnancy after lung transplant highlights a number of salient points. First, our results are similar to those of other studies, which demonstrate that pregnancy can be achieved after lung transplantation. Our rate of full-term delivery (42%) is similar to the 56% recently reported by Shaner et al2 and previously by Nair et al.6 Pregnancy continues to be an uncommon issue in our large center, and it is only ever recommended in stable patients who approach us and are aware of its inherent risks. However, with increasing numbers of successful pregnancies after transplant being reported, this issue has become more prominent in our clinics. We do make a number of recommendations to our Table 3
patients considering pregnancy based on our local experience and published data (Table 4). Our advice to patients is to avoid conception for at least the first 2 years after transplant to mitigate the risk of higher levels of immunosuppression used early after transplant and to allow time to evaluate for complications that may arise by lowering immunosuppression; this is in keeping with previous expert consensus recommendations.7 Indeed, our patients conceived at a mean of more than 6 years after transplant, with the shortest duration being 26 months after transplant. In addition, we advise all patients to plan pregnancy and to use reliable contraception at all other times. Immunosuppression is altered in planned pregnancies, such that we advocate the use of a CNI, prednisone, and azathioprine. Mycophenolate mofetil is generally stopped according to previous guidelines.17 Despite mycophenolate mofetil and azathioprine both being Food and Drug Administration Class D with respect to use in pregnancy, experience with azathioprine is greater, and hence, its preference in our center.18 Tacrolimus, cyclosporine, and prednisolone are all considered Class C medications, and therefore, their use is continued through pregnancy. We recommend against pregnancy if other class D drugs, such as voriconazole, need to be used for treatment.18 One unplanned pregnancy did occur while a patient was on methotrexate (Class X)18; unfortunately, this patient also had unstable lung function, and ultimately, a therapeutic termination was required. Conception was clearly impaired in our population, with 21% requiring assistance in the form of medications or
(B) Changes in Kidney Function and Cyclosporine A Doses/Levels Through Pregnancya Patient 5
Patient 9
Assessmentb
Cr (μmol/ liter)
CyA level
Baseline 1st trimester 3rd trimester
153 114 160
304 134 115
Total CyA Cr (μmol/ daily dose (mg) liter) 1,000 850 850
163 174 175
Patient 10 CyA level
Total CyA daily Cr (μmol/ dose (mg) liter)
CyA level
Total CyA daily dose (mg)
204 160 114
400 350 350
121 114 127
275 275 275
218 168 166
CyA, cyclosporine A; Tac, tacrolimus. a Number of patients are too low to calculate meaningful p-values. b Baseline collected 2–12 weeks before conception, 1st trimester collected before 12 weeks gestation, 3rd trimester is the last testing before delivery (26–35 weeks’ gestation).
Thakrar et al. Table 4
Pregnancy After Transplantation
Recommendations to Patients Regarding Pregnancy
Period
Recommendations
Pre-pregnancy
Pregnancy
Post-pregnancy
Minimum 2 years after transplant Contraception is needed until planned pregnancy Must be free of BOS or recurrent acute rejection Must be free of infectious comorbidities Immunosuppression should be azathioprine, CNI, prednisone Advised that complications are common Consider screening partners of cystic fibrosis patients Frequent checks of CNI level and renal function Frequent spirometry Multidisciplinary care is key Infectious complications are common Rejection and BOS may occur and need to be watched for Delivery to term occurs in less than 50% of pregnancies Death of the mother may occur
BOS, bronchiolitis obliterans syndrome; CNI, calcineurin inhibitor.
in vitro fertilization. Current guidelines in the United Kingdom do not specifically comment on the use of these techniques,14 but in our experience, and according to the same guidelines, referral to specialized fertility physicians is required. Two of our 3 patients who required therapies to achieve conception were cystic fibrosis patients, in whom fertility may be impaired by virtue of their underlying disease.10 Also, all patients requiring assistance were older than 30 years, which may have had a significant bearing on fertility, although even at the age 35, 94% of healthy women will conceive within 3 years of regular sexual intercourse.14 As far as we can tell, there are no data regarding the safety of any fertility treatments in solidorgan transplant recipients or regarding interactions with immunosuppression and other transplant related medications. However, no patients in our cohort who underwent fertility treatments actually conceived and delivered a term infant, suggesting that these therapies may not be of benefit in this patient population. It could be postulated that impaired fertility in this group may point to underlying medical disorders that would make full-term pregnancy difficult to achieve. As illustrated by others,2,3 complications were seen commonly in our center, with infections predominating (21%). Although 2 of the 3 infections were communityacquired pneumonia that responded well to first-line antibiotics, this complication included highly infective tuberculosis of the larynx in 1 patient. Cure was achieved with 6 months of usual anti-tuberculosis therapy. Shaner et al2 also showed a similar rate of infection in their patients. The high rates of infection in this group may represent the additive effects of immunosuppressive medications and pregnancy itself15,16 on reducing CD4 cell function. None of our center’s patients received induction immunosuppression at the time of transplant, and so this increased infection rate
597 is not related to iatrogenic alterations in CD4 function aside from standard immunosuppression regimens used after transplant. Previous studies have reported that FEV1 falls in healthy women in the third trimester, and that FVC usually does not.11,12 This study, which examined changes in lung function of lung transplant recipients during pregnancy, found that spirometry did not change through pregnancy, aside from 1 woman who developed severe BOS. This leads us to conclude that falls in spirometry during pregnancy in a lung transplant patient likely represent true pathology and need to be investigated as an abnormal finding, in contrast to what is seen in healthy pregnant women. A fall in FEV1 or FVC should not be considered a normal change in pregnancy in this group. We investigated falls in lung function in these patients with chest X-ray (shielded to protect the fetus) and bronchoscopy with transbronchial biopsies, in exactly the same manner as other transplant patients. The reason FEV1 does not fall in pregnant transplant recipients, compared with non-transplant pregnant women, is not entirely clear. There is evidence to suggest babies born to transplant recipients are smaller,7 so perhaps the smaller gravid uterus exerts less effect on pulmonary flow rates. Similarly, the changes in glomerular filtration rate in healthy individuals have been studied,13 but to the best of our knowledge, these effects have not been studied in lung transplant recipients who become pregnant. We have demonstrated that a fall in creatinine is evident in this group, even while on CNI therapy. However, this change was extremely variable in our patient group, and therefore, we recommend frequent blood work in our patients to monitor renal function throughout pregnancy. Many transplant physicians have previously been concerned about falling renal function in this group, but this was not seen in our cohort with good blood pressure control throughout most of their pregnancies. In addition, our data suggest that a fall in the trough CNI level can be expected in the first trimester and that drug dosing should be adjusted accordingly. Drug levels should be monitored frequently throughout pregnancy. It is theoretically possible for nausea gravidarum or hyperemesis gravidarum to alter drug absorption, and hence, CNI levels in the first trimester, but these symptoms should resolve in most patients by 20 weeks,19 whereas lowered CNI levels were seen throughout entire pregnancies. It is just as possible that falls in CNI levels seen later in pregnancy are related to increases in circulating plasma volumes and alterations in renal blood flow throughout pregnancy.17 This hypothesis could be supported by the fact that tacrolimus trough levels fell to a greater degree than cyclosporine levels in our study. The volume of distribution of tacrolimus is more then 10 times greater than cyclosporine to begin with,20,21 and perhaps as plasma volume expands, this difference becomes even more apparent. As such, one could propose that monitoring cyclosporine levels during pregnancy is not as crucial as tacrolimus levels. We, however, recommend obtaining a CNI trough level as soon as pregnancy is confirmed, regardless of the agent, and then every 2 weeks (weekly if dose alterations are made). This study has some limitations. Its retrospective nature and single-center viewpoint limit interpretation of the data.
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Although our data appear to mirror recent publications,2 they also provide observations on trends in lung and renal function suggesting that this information can certainly add to the body of evidence. In addition, the small numbers of patients in our cohort limit statistical analysis, but interesting trends are evident that should prompt further study. Finally, because mothers delivered at centers throughout the United Kingdom, and not necessarily at our institution, we are unable to gather data on delivery and infant outcomes. Although the North American experience with pregnancy after transplantation is extensive,4 most of this evidence comes from renal transplant recipients. In the context of lung and heart-lung transplantation, experience is still growing, with individual centers reporting their data.2,6,8,22 It appears as though less than 100 pregnancies have been reported in lung and heart-lung transplant recipients, whereas the National Transplant Pregnancy Registry alone has more than 1,200 pregnancies in renal transplant patients.4 Given the poorer long-term outcomes and increased rates of comorbidities in lung transplant recipients, this group needs to be considered separately. We would propose the idea that international data collection regarding this ever-increasing issue, in this specific population, occur through organizations such as the International Society of Heart and Lung Transplantation. In conclusion, we have demonstrated that patients can deliver full-term babies after lung transplantation. Their course through pregnancy does yield specific complications that necessitate the need for a multidisciplinary approach involving nurses, transplant physicians, and obstetricians. However, lung function can successfully be maintained through pregnancy. There appear to be significant changes in renal physiology and CNI pharmacokinetics that require close serial monitoring to ensure adequate immunosuppression. Further studies are required to allow for guideline development in this sphere.
2. 3. 4.
5. 6.
7.
8.
9. 10. 11. 12. 13.
14.
15.
16.
Disclosure statement M.V.T. received funding to undertake this research from the Division of Respiratory Medicine at the University of Calgary. A portion of this study was presented at the Thirty-third Annual Meeting and Scientific Sessions of the International Society for Heart and Lung Transplantation, Montreal, Quebec, Canada, April 24–27, 2013. None of the authors has a financial relationship with a commercial entity that has an interest in the subject of the presented manuscript or other conflicts of interest to disclose.
17.
18. 19. 20.
21.
References 22. 1. Christie JD, Edwards LB, Kucheryavaya AY, et al. The Registry of the International Society for Heart and Lung Transplantation: twenty-eighth
adult lung and heart-lung transplant report—2011. J Heart Lung Transplant 2011;30:1104-22. Shaner J, Coscia L, Constantinescu S, et al. Pregnancy after lung transplantation. Prog Transplant 2012;22:134-40. McKay DB, Josephson MA. Pregnancy in recipients of solid organs— effects on mother and child. N Engl J Med 2006;354:1281-93. Coscia LA, Constantinescu S, Moritz MJ, et al. Report from the National Transplantation Pregnancy Registry (NTPR): outcomes of pregnancy after transplantation. Clin Transpl 2010:65-85. Mastrobattista JM, Katz AR. Pregnancy after organ transplant. Obstet Gyncol Clin North Am 2004;31:415-28. Nair KS, Ghosh KA, Mooney A, et al. Maternal and foetal outcome following pregnancy after intrathoracic organ transplantation: a single centre experience in 21 patients. J Heart Lung Transplant 2003; 22(1 Suppl):S160. McKay DB, Josephson MA, Armenti VT, et al. Reproduction and transplantation: report on the AST Consensus Conference on Reproductive Issues and Transplantation. Am J Transplant 2005;5:1592-9. Gyi KM, Hodson ME, Yacoub MY. Pregnancy in cystic fibrosis lung transplant recipients: case series and review. J Cyst Fibros 2006;5: 171-5. Budev MM, Arroliga AC, Emery S. Exacerbation of underlying pulmonary disease in pregnancy. Crit Care Med 2005;33:313-8. Kotloff RM, FitzSimmons SC, Fiel SB. Fertility and pregnancy in patients with cystic fibrosis. Clin Chest Med 1992;13:623-35. Norregaard O, Schultz P, Ostergaard A, Dahl R. Lung function and postural changes during pregnancy. Respir Med 1989;83:467-70. Weinberger SE, Weiss ST, Cohen WR, Weiss JW, Johnson TS. Pregnancy and the lung. Am Rev Respir Dis 1980;121:559-77. Krutzen E, Olofsson P, Back SE, Nilsson-Ehle P. Glomerular filtration rate in pregnancy: a study in normal subjects and in patients with hypertension, preeclampsia and diabetes. Scan J Clin Lab Invest 1992;52:387-92. National Institute of Health and Clinical Excellence (NICE). CG 11: Fertility: assessment and treatment for people with fertility problems. http://guidance.nice.org.uk/CG156. Accessed October 30, 2012. Stagnaro-Green A, Roman SH, Cobin RH, el-Harazy E, Wallenstein S, Davies TF. A prospective study of lymphocyte-initiated immunosuppression in normal pregnancy: evidence of a T-cell etiology for postpartum thyroid dysfunction. J Clin Endocrinol Metab 1992;74: 645-53. Borzychowski AM, Croy BA, Chan WL, Redman CW, Sargent IL. Changes in systemic type 1 and type 2 immunity in normal pregnancy and pre-eclampsia may be mediated by natural killer cells. Eur J Immunol 2005;35:3054-63. Costanzo MR, Dipchand A, Starling R, et al. The International Society of Heart and Lung Transplantation guidelines for the care of heart transplant recipients. J Heart Lung Transplant 2010;29:914-56. Drugs.com website. Medicine use during pregnancy or breastfeeding. http://www.drugs.com/pregnancy. Accessed November 13, 2013. Verberg MF, Gillott DJ, Al-Fardan N, Grudzinskas JG. Hyperemesis gravidarum, a literature review. Hum Reprod Update 2005;11:527-39. Antignac A, Barrou B, Farinotti R, et al. Population pharmacokinetics and bioavailability or tacrolimus in kidney transplant patients. Br J Clin Pharmacol 2007;64:750-7. Lill J, Bauer LA, Horn J, Hansten PD. Cyclosporine-drug interactions and the influence of patient age. Am. J. Health Syst Pharm 2000;57: 1579-84. Zurbano F, Lopez F, Fornet I, de Miguel JR, Segovia J, Ussetti P. Maternity and lung transplantation: cases in Spain. Arch Bronconeumol 2012;48:379-81.
Pregnancy after lung and heart-lung transplantation Mitesh V. Thakrar, MD,a,b Katie Morley, RN,a James L. Lordan, MD,a Gerard Meachery, MD,a Andrew J. Fisher, MD,a Gareth Parry, MD,a and Paul A. Corris, MDa From the aCardiopulmonary Transplantation, Institute of Transplantation, Institute of Cellular Medicine, Newcastle University and The Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, United Kingdom; and the bDepartment of Medicine, Division of Pulmonary Medicine, Southern Alberta Lung Transplant Program, University of Calgary, Calgary, Alberta, Canada.
KEYWORDS: transplantation; pregnancy; calcineurin inhibitor; spirometry; renal function
BACKGROUND: Advances in lung transplantation have enabled women to successfully undertake pregnancies. This study explored outcomes in this group, including changes in lung function, kidney function, and calcineurin inhibitor (CNI) levels. METHODS: A retrospective review identified 19 transplant recipients who had ever become pregnant at our center, and manual reviews of their medical records were completed for 14. Results of spirometry, serum creatinine, CNI doses and trough levels, and comorbidities were collected. RESULTS: Eight births occurred (42% success rate). Six patients have since died, with pregnancy contributing to 1 death. Five pregnancies were unplanned, with only 1 resulting in birth. Six pregnancies ended with spontaneous termination, and 2 were terminated for medical reasons. Mean age was 31.4 years (range, 22–39 years), and mean time from transplant was 76.2 months (range, 26–139 months). Complications included preeclampsia in 2, diabetes of pregnancy in 1, and abnormal liver enzymes in 1. Within 6 months of delivery, there were 2 cases of pneumonia, 2 cases of obliterative bronchiolitis, 1 case of tuberculosis, and 1 case of mild acute rejection. Forced expiratory volume in 1 second was stable at 3 (–1.5%; p ¼ 0.55) and 12 months (1.4%; p ¼ 0.84) after pregnancy. Mean change in Forced expiratory volume in 1 second during full-term pregnancies was –2.4% (p ¼ 0.29), and the mean change in forced vital capacity was –0.8% (p ¼ 0.55). In the first trimester, 83% of patients had a fall in creatinine, and a universal fall in CNI trough levels was seen. CONCLUSIONS: In carefully selected patients, planned pregnancy after lung transplant can be successful. Complications are common, and close monitoring of immunosuppression and renal function is needed. J Heart Lung Transplant 2014;33:593–598 r 2014 International Society for Heart and Lung Transplantation. All rights reserved.
Lung transplantation has become an ever-increasing option in the management of end-stage lung diseases, with steadily improving outcomes.1 These advances have allowed women of childbearing age to successfully undertake pregnancies, with delivery of healthy infants, but with significantly a higher risk than the general population.2–6 Given these higher risks, it has Reprint requests: Mitesh V. Thakrar, MD, University of Calgary, Peter Lougheed Hospital, 3500 26 Ave NE, Calgary, AB T1Y 6J4, Canada. Telephone: þ1-403-943-4833. Fax: þ1-403-943-4017. E-mail address: [email protected]
been advised that pregnancies should be planned in advance in this group and that teratogenic medications, such as mycophenolate mofetil, be stopped before conception.7 Furthermore, it has been advised that pregnancies should be avoided until at least 1 to 3 years after transplant.7–9 The literature remains rather scarce on a clear policy and outcomes after pregnancy in lung transplant recipients, so we present our own experience. We hypothesized that patients could successfully deliver term infants, but that significant complications might be evident through pregnancy and after. The purpose of this
1053-2498/$ - see front matter r 2014 International Society for Heart and Lung Transplantation. All rights reserved. http://dx.doi.org/10.1016/j.healun.2014.02.008
594
The Journal of Heart and Lung Transplantation, Vol 33, No 6, June 2014
study was to contribute to an area that requires further knowledge and improve our understanding of maternal outcomes with pregnancy, with a particular focus on changes in physiology, such as lung function, kidney function, and calcineurin inhibitor (CNI) levels, which may have a bearing on future graft function.
Methods A retrospective audit of all lung transplants ever conducted at the Freeman Hospital in Newcastle upon Tyne was undertaken. Searches of the local database identified all patients who had ever become pregnant, and their medical records were manually reviewed. Results of lung function testing, serum creatinine, CNI doses and trough levels, and any comorbidities encountered were collected. Changes in spirometry over time were compared with baseline, with calculations of 95% confidence intervals (CIs) made using Excel software (Microsoft Corp, Redmond, WA). This study was classified as an audit of clinical practice, and given that all patient information was anonymous, application to the local Ethics Review Board was not necessary according to local policy.
Results In more than 25 years’ experience, there have been 827 transplants (lung and heart-lung transplants) in 816 patients. Of these, 253 were women aged younger than 40 years, among whom there have been 19 pregnancies amongst 16 patients, leading to 8 live births (42% success rate). Complete medical records were available for 14 pregnancies, of which 6 were successful. Of the other 8 pregnancies, 6 ended in spontaneous terminations, and 2 required termination due to medical reasons (1 ectopic pregnancy and 1 unplanned pregnancy in a patient with poor lung function). Available records showed that 3 of the 14 pregnancies (21%) required assistance with fertility treatments, all of whom were aged older than 30 years. Patient 1 attempted in vitro fertilization and ultimately conceived naturally. Table 1
Patients 7 and 8 used medications to improve fertility; however, their 2 pregnancies resulted in miscarriage. Six patients died after their pregnancies, and 8 mothers remain alive (range, 3–197 months post-partum). Death in 1 patient occurred 8 months after delivery, with the patient presenting with rapidly progressive bronchiolitis obliterans syndrome (BOS) and an unplanned pregnancy at the same time; it appears as though this is the only patient in our series in whom death may be partly attributable to pregnancy. Mean age at the time of pregnancy was 31.4 years (range 22–39 years), and mean time from transplant was 76.2 months (range 26–139 months; Table 1). Immunosuppressive regimens were varied and included combinations of tacrolimus in 8, cyclosporine A in 6, azathioprine in 6, prednisone in 10, and methotrexate in 1 (unplanned pregnancy; Table 1). Most patients (93%) had pre-existing medical comorbid conditions, medical conditions that arose during pregnancy, or post-partum medical concerns. Pre-pregnancy complications included chronic kidney disease (50%), diabetes (29%), genital warts (7%), and BOS (21%, all unplanned pregnancies; Table 2). In the cases of pre-existing BOS, 1 patient became pregnant with no prior discussion about pregnancy with the transplant center. In her situation, a medically indicated termination was performed after the risks of pregnancy were outlined to her and her partner and consent was obtained. In the other patient, 2 unplanned pregnancies occurred, one of which ended in a spontaneous abortion, whereas the second delivery was successful. However, rapidly progressive BOS resulting in death complicated the pregnancy and post-partum period. Complications during pregnancy included preeclampsia in 2 (14%), diabetes of pregnancy in 1 (7%), and abnormal liver enzymes in 1 (7%). Within 6 months of delivery, there were 3 infections (21%), 3 cases of BOS (21%), and 1 mild acute rejection (7%) that did not require steroid augmentation (Table 2). With respect to the infections
Maternal Characteristics
Pt
Months post-Tx
Age at pregnancy (years)
Type of Tx
Indication for Tx
Immunosuppression
Planned or unplanned Pregnancy
1 2 3 4 5 6 7 8 9 10 11 12 13 14
139 26 71 48 62 67 126 42 60 78 119 107 101 63
39 23 38 28 29 22 39 32 37 39 37 26 31 20
SSLTx SSLTx SSLTx SSLTx SSLTx HLTx HLTx SSLTx HLTx HLTx SSLTx HLTx HLTx HLTx
Cystic fibrosis Cystic fibrosis Cystic fibrosis Cystic fibrosis Cystic fibrosis Congenital heart Congenital heart Cystic fibrosis Asthma Asthma Cystic fibrosis CTEPH Congenital heart Cystic fibrosis
Tac Tac, Pred Tac, Pred, Aza CyA, Pred, Aza CyA, Pred, Aza Mtx, CyA, Pred CyA Tac, Pred, CyA CyA, Pred CyA, Pred Tac Tac, Aza, Pred Tac, Aza Tac, Pred, Aza
Unplanned Unplanned Planned Planned Planned Unplanned Planned Planned Planned Planned Unplanned Unplanned Planned Planned
Aza, azathioprine; CyA, cyclosporine A; CTEPH, chronic thromboembolic pulmonary hypertension; HLTx, heart and lung transplant; Mtx, methotrexate; Pred, prednisone; Pt, patient; SSLTx, single sequential lung transplant; Tac, tacrolimus; Tx, transplant.
Thakrar et al. Table 2
Pregnancy After Transplantation
595
Pregnancy Outcomes Complications
Pt
Pre-existing conditions
During pregnancy
After delivery
Outcomea
1 2 3 4 5 6 7 8 9 10 11 12 13 14
BOS, ISHLT stage 1 DM CKD sage 3 CKD sage 3, DM CKD stage 3, DM BOS, ISHLT stage 3 CKD stage 3 CKD stage 3 CKD stage 3 CKD stage 4 BOS, ISHLT stage 1 Genital and peri-anal warts
DM
Pneumonia, rapid BOS
Birth Birth Miscarriage at 11 weeks Miscarriage at 12 weeks Birth Termination Termination at 6 weeks Miscarriage at 12 weeks Birth Birth Miscarriage 16 weeks Miscarriage Birth Miscarriage
A1B2 rejection Active tuberculosis Abnormal liver enzymes Worsened BOS; required TLI Ectopic pregnancy Pneumonia, BOS Preeclampsia Preeclampsia
GERD, DM
BOS
BOS, bronchiolitis obliterans syndrome; CKD, chronic kidney disease; DM, diabetes mellitus; GERD, gastroesophageal reflux disease; ISHLT, International Society of Heart and Lung Transplantation; TLI, total lymphoid irradiation. a Termination indicates medical termination; miscarriage indicates spontaneous abortion.
encountered, 2 cases of bacterial pneumonia were seen, which were easily treated with antibiotics. The third was a case of highly infectious, but fully susceptible, tuberculosis of the larynx that required 6 months of therapy, and subsequent cure was achieved. In the cases of post-partum BOS, lung function stabilized spontaneously in 2 patients with BOS stage 1. In the other, total lymphoid irradiation was required to halt progression of BOS. In patients with full-term pregnancies and in those with terminated pregnancies, spirometry nearest the time of conception was similar to that obtained at 3 and 12 months after pregnancy in all but 1 patient (Figure 1). Excluding Patient 1, who presented with severe and rapid BOS at the onset of pregnancy, mean changes in forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) at 3 months after pregnancy in all comers were, compared with baseline, –1.5% (median, –1.78%; 95% CI, –8.5% to
5.5%), and 1.4% (median, –0.35%; 95% CI, –5.0% to 7.7%), respectively (Figure 1). Similarly, at 12 months after pregnancy, mean changes in FEV1 and FVC were 1.1% (median, –1.3%; 95% CI, –3.6% to 5.8%) and 2.1% (median, –0.38%; 95% CI, –6.2% to 10.3%) compared with baseline, respectively (Figure 1). In the 6 live births that occurred, as described above, 1 patient had a severe drop in her FEV1 and FVC related to rapidly progressive BOS. However, in the remaining 5 pregnancies, lung function was relatively stable when the last spirometry measurement during pregnancy was compared with the value approximately 1 year before conception. This final gestational spirometry measurement occurred between 25 and 36 weeks’ gestation in this group. Mean change in FEV1 during pregnancy compared with baseline was –2.4% (median, –5.0%; 95% CI, –11.3% to 6.5%), and mean change in FVC was –0.8% (median,
10
Percentage Change in Spirometry
0 -10 -20 -30 -40 -50 -60 -70 -80 Baseline
Delivery Patient 1 FEV1
Patient 1 FVC
3 months post All Others FEV1
12 months post All Others FVC
Figure 1 Percentage change in spirometry after pregnancy compared with before conception in all patients. FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity.
596 Table 3
The Journal of Heart and Lung Transplantation, Vol 33, No 6, June 2014 (A) Changes in Kidney Function and Tacrolimus Doses/Levels Through Pregnancya Patient 1
Patient 2
Patient 13
Assessmentb
Cr (μmol/ liter)
Tac level
Total tac daily dose (mg)
Cr (μmol/ liter)
Tac level
Total tac daily dose (mg)
Cr (μmol/liter)
Tac level
Total tac daily dose (mg)
Baseline 1st trimester 3rd trimester
109 78 76
11.1 4 6.3
4 4 5
110 102 112
9 3.2 7.4
7 7 9
98 79 74
9.3 9.1 4.5
4 4 5
Tac, tacrolimus. a Number of patients are too low to calculate meaningful p-values. b Baseline collected 2–12 weeks before conception, 1st trimester collected before 12 weeks gestation, 3rd trimester is the last testing before delivery (26–35 weeks’ gestation).
–1.3%; 95% CI, –9.2% to 7.5%). Patients with terminations were not included in this analysis because none had spirometry in the second or third trimesters. In contrast to relatively stable lung function in these pregnancies, there was evidence of changes in serum creatinine and CNI levels. In the first trimester, creatinine fell in 5 patients, and there was a significant fall in drug levels in 5 patients. In patients receiving tacrolimus, total daily doses were increased 20% to 37.5%, although trough levels still did not meet pre-pregnancy levels (Table 3A). In contrast, those receiving cyclosporine A appeared to not receive dose adjustments, and their trough levels remained lower than baseline throughout pregnancy (Table 3B).
Discussion This review of a single center’s experience in pregnancy after lung transplant highlights a number of salient points. First, our results are similar to those of other studies, which demonstrate that pregnancy can be achieved after lung transplantation. Our rate of full-term delivery (42%) is similar to the 56% recently reported by Shaner et al2 and previously by Nair et al.6 Pregnancy continues to be an uncommon issue in our large center, and it is only ever recommended in stable patients who approach us and are aware of its inherent risks. However, with increasing numbers of successful pregnancies after transplant being reported, this issue has become more prominent in our clinics. We do make a number of recommendations to our Table 3
patients considering pregnancy based on our local experience and published data (Table 4). Our advice to patients is to avoid conception for at least the first 2 years after transplant to mitigate the risk of higher levels of immunosuppression used early after transplant and to allow time to evaluate for complications that may arise by lowering immunosuppression; this is in keeping with previous expert consensus recommendations.7 Indeed, our patients conceived at a mean of more than 6 years after transplant, with the shortest duration being 26 months after transplant. In addition, we advise all patients to plan pregnancy and to use reliable contraception at all other times. Immunosuppression is altered in planned pregnancies, such that we advocate the use of a CNI, prednisone, and azathioprine. Mycophenolate mofetil is generally stopped according to previous guidelines.17 Despite mycophenolate mofetil and azathioprine both being Food and Drug Administration Class D with respect to use in pregnancy, experience with azathioprine is greater, and hence, its preference in our center.18 Tacrolimus, cyclosporine, and prednisolone are all considered Class C medications, and therefore, their use is continued through pregnancy. We recommend against pregnancy if other class D drugs, such as voriconazole, need to be used for treatment.18 One unplanned pregnancy did occur while a patient was on methotrexate (Class X)18; unfortunately, this patient also had unstable lung function, and ultimately, a therapeutic termination was required. Conception was clearly impaired in our population, with 21% requiring assistance in the form of medications or
(B) Changes in Kidney Function and Cyclosporine A Doses/Levels Through Pregnancya Patient 5
Patient 9
Assessmentb
Cr (μmol/ liter)
CyA level
Baseline 1st trimester 3rd trimester
153 114 160
304 134 115
Total CyA Cr (μmol/ daily dose (mg) liter) 1,000 850 850
163 174 175
Patient 10 CyA level
Total CyA daily Cr (μmol/ dose (mg) liter)
CyA level
Total CyA daily dose (mg)
204 160 114
400 350 350
121 114 127
275 275 275
218 168 166
CyA, cyclosporine A; Tac, tacrolimus. a Number of patients are too low to calculate meaningful p-values. b Baseline collected 2–12 weeks before conception, 1st trimester collected before 12 weeks gestation, 3rd trimester is the last testing before delivery (26–35 weeks’ gestation).
Thakrar et al. Table 4
Pregnancy After Transplantation
Recommendations to Patients Regarding Pregnancy
Period
Recommendations
Pre-pregnancy
Pregnancy
Post-pregnancy
Minimum 2 years after transplant Contraception is needed until planned pregnancy Must be free of BOS or recurrent acute rejection Must be free of infectious comorbidities Immunosuppression should be azathioprine, CNI, prednisone Advised that complications are common Consider screening partners of cystic fibrosis patients Frequent checks of CNI level and renal function Frequent spirometry Multidisciplinary care is key Infectious complications are common Rejection and BOS may occur and need to be watched for Delivery to term occurs in less than 50% of pregnancies Death of the mother may occur
BOS, bronchiolitis obliterans syndrome; CNI, calcineurin inhibitor.
in vitro fertilization. Current guidelines in the United Kingdom do not specifically comment on the use of these techniques,14 but in our experience, and according to the same guidelines, referral to specialized fertility physicians is required. Two of our 3 patients who required therapies to achieve conception were cystic fibrosis patients, in whom fertility may be impaired by virtue of their underlying disease.10 Also, all patients requiring assistance were older than 30 years, which may have had a significant bearing on fertility, although even at the age 35, 94% of healthy women will conceive within 3 years of regular sexual intercourse.14 As far as we can tell, there are no data regarding the safety of any fertility treatments in solidorgan transplant recipients or regarding interactions with immunosuppression and other transplant related medications. However, no patients in our cohort who underwent fertility treatments actually conceived and delivered a term infant, suggesting that these therapies may not be of benefit in this patient population. It could be postulated that impaired fertility in this group may point to underlying medical disorders that would make full-term pregnancy difficult to achieve. As illustrated by others,2,3 complications were seen commonly in our center, with infections predominating (21%). Although 2 of the 3 infections were communityacquired pneumonia that responded well to first-line antibiotics, this complication included highly infective tuberculosis of the larynx in 1 patient. Cure was achieved with 6 months of usual anti-tuberculosis therapy. Shaner et al2 also showed a similar rate of infection in their patients. The high rates of infection in this group may represent the additive effects of immunosuppressive medications and pregnancy itself15,16 on reducing CD4 cell function. None of our center’s patients received induction immunosuppression at the time of transplant, and so this increased infection rate
597 is not related to iatrogenic alterations in CD4 function aside from standard immunosuppression regimens used after transplant. Previous studies have reported that FEV1 falls in healthy women in the third trimester, and that FVC usually does not.11,12 This study, which examined changes in lung function of lung transplant recipients during pregnancy, found that spirometry did not change through pregnancy, aside from 1 woman who developed severe BOS. This leads us to conclude that falls in spirometry during pregnancy in a lung transplant patient likely represent true pathology and need to be investigated as an abnormal finding, in contrast to what is seen in healthy pregnant women. A fall in FEV1 or FVC should not be considered a normal change in pregnancy in this group. We investigated falls in lung function in these patients with chest X-ray (shielded to protect the fetus) and bronchoscopy with transbronchial biopsies, in exactly the same manner as other transplant patients. The reason FEV1 does not fall in pregnant transplant recipients, compared with non-transplant pregnant women, is not entirely clear. There is evidence to suggest babies born to transplant recipients are smaller,7 so perhaps the smaller gravid uterus exerts less effect on pulmonary flow rates. Similarly, the changes in glomerular filtration rate in healthy individuals have been studied,13 but to the best of our knowledge, these effects have not been studied in lung transplant recipients who become pregnant. We have demonstrated that a fall in creatinine is evident in this group, even while on CNI therapy. However, this change was extremely variable in our patient group, and therefore, we recommend frequent blood work in our patients to monitor renal function throughout pregnancy. Many transplant physicians have previously been concerned about falling renal function in this group, but this was not seen in our cohort with good blood pressure control throughout most of their pregnancies. In addition, our data suggest that a fall in the trough CNI level can be expected in the first trimester and that drug dosing should be adjusted accordingly. Drug levels should be monitored frequently throughout pregnancy. It is theoretically possible for nausea gravidarum or hyperemesis gravidarum to alter drug absorption, and hence, CNI levels in the first trimester, but these symptoms should resolve in most patients by 20 weeks,19 whereas lowered CNI levels were seen throughout entire pregnancies. It is just as possible that falls in CNI levels seen later in pregnancy are related to increases in circulating plasma volumes and alterations in renal blood flow throughout pregnancy.17 This hypothesis could be supported by the fact that tacrolimus trough levels fell to a greater degree than cyclosporine levels in our study. The volume of distribution of tacrolimus is more then 10 times greater than cyclosporine to begin with,20,21 and perhaps as plasma volume expands, this difference becomes even more apparent. As such, one could propose that monitoring cyclosporine levels during pregnancy is not as crucial as tacrolimus levels. We, however, recommend obtaining a CNI trough level as soon as pregnancy is confirmed, regardless of the agent, and then every 2 weeks (weekly if dose alterations are made). This study has some limitations. Its retrospective nature and single-center viewpoint limit interpretation of the data.
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The Journal of Heart and Lung Transplantation, Vol 33, No 6, June 2014
Although our data appear to mirror recent publications,2 they also provide observations on trends in lung and renal function suggesting that this information can certainly add to the body of evidence. In addition, the small numbers of patients in our cohort limit statistical analysis, but interesting trends are evident that should prompt further study. Finally, because mothers delivered at centers throughout the United Kingdom, and not necessarily at our institution, we are unable to gather data on delivery and infant outcomes. Although the North American experience with pregnancy after transplantation is extensive,4 most of this evidence comes from renal transplant recipients. In the context of lung and heart-lung transplantation, experience is still growing, with individual centers reporting their data.2,6,8,22 It appears as though less than 100 pregnancies have been reported in lung and heart-lung transplant recipients, whereas the National Transplant Pregnancy Registry alone has more than 1,200 pregnancies in renal transplant patients.4 Given the poorer long-term outcomes and increased rates of comorbidities in lung transplant recipients, this group needs to be considered separately. We would propose the idea that international data collection regarding this ever-increasing issue, in this specific population, occur through organizations such as the International Society of Heart and Lung Transplantation. In conclusion, we have demonstrated that patients can deliver full-term babies after lung transplantation. Their course through pregnancy does yield specific complications that necessitate the need for a multidisciplinary approach involving nurses, transplant physicians, and obstetricians. However, lung function can successfully be maintained through pregnancy. There appear to be significant changes in renal physiology and CNI pharmacokinetics that require close serial monitoring to ensure adequate immunosuppression. Further studies are required to allow for guideline development in this sphere.
2. 3. 4.
5. 6.
7.
8.
9. 10. 11. 12. 13.
14.
15.
16.
Disclosure statement M.V.T. received funding to undertake this research from the Division of Respiratory Medicine at the University of Calgary. A portion of this study was presented at the Thirty-third Annual Meeting and Scientific Sessions of the International Society for Heart and Lung Transplantation, Montreal, Quebec, Canada, April 24–27, 2013. None of the authors has a financial relationship with a commercial entity that has an interest in the subject of the presented manuscript or other conflicts of interest to disclose.
17.
18. 19. 20.
21.
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